Duchenne's muscular dystrophy (DMD) is a common, fatal, genetic disease estimated to affect 1 in 3500 live-born males. Currently no definitive therapy exists for DMD providing an impetus for urgently developing therapies. DMD is caused by mutations in the DMD gene leading to an absence of the dystrophin protein. Utrophin (dystrophin-related protein/DRP) is the autosomal homolog of dystrophin sharing extensive sequence similarity and organizational motifs with dystrophin. It has been shown that utrophin up-regulation can functionally substitute for the missing dystrophin and ameliorate the dystrophic phenotype of the mdx animal model of DMD, hence is considered a promising therapeutic approach. Modest degrees of upregulation have been achieved using transcription activators; however, it is unclear is transcriptional upregulation will suffice in the clinical therapeutic context, since utrophin is regulated at both transcriptional and post-transcriptional levels. We and others have shown that post-transcriptional mechanisms, mediated by the 5' and 3' untranslated regions (UTRs), have a profound effect on utrophin expression and offer a potential target for DMD therapeutic strategies. Here we propose a collaboration to develop and screen a cell-based assay using High Throughput Screening (HTS) to discover, develop and validate small molecules that increase utrophin expression by targeting this key phase of regulation. These studies would identify novel small molecules with great potential for development into DMD therapeutics.